The goal of this project of four unique heterocyclic scaffolds for library development, each displaying a minimum of three orthogonal diversification points for derivatization which can be moved positionally within the scaffold structure. Each scaffold also bears stereocenters which can be constructed with high degrees of selectivity to allow for additional stereochemical diversity. The four parent scaffolds are: (1), 1,7-dioxaspiro[5,5]undecane spiroketals; (2) pipecolic acids; (3) flavonoids; (4) 1,2,3,4-tetrahydro-1,5-naphthyridines, thus representing two oxygen heterocycles and two nitrogen heterocycles. The goal is to produce a variety of libraries with a limited number of members, rather than fewer libraries with a large numbers of structurally repetitive members. Two libraries will be produced using the spiroketal scaffold, three libraries from the pipecolic acid core structure, and four libraries each from the flavonoid and naphthyridine heterocycles. The emphasis within this project will also be on the development of new methodologies for use in chemical library construction. Thus within each subproject defined by the four unique scaffolds, new resin-bound reagents, scavenger resins for reaction work-up, and new capture-and-release strategies are proposed for development. The individual library constructions stress original synthetic strategies that lead to conformationally biased heterocycles that expand stereochemical and positional diversity as they probe three dimensional space.